EP0426826B1 - Substituted isoxazolidines and isoxazolines - Google Patents
Substituted isoxazolidines and isoxazolines Download PDFInfo
- Publication number
- EP0426826B1 EP0426826B1 EP90908724A EP90908724A EP0426826B1 EP 0426826 B1 EP0426826 B1 EP 0426826B1 EP 90908724 A EP90908724 A EP 90908724A EP 90908724 A EP90908724 A EP 90908724A EP 0426826 B1 EP0426826 B1 EP 0426826B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- propylpentyl
- compounds
- optionally
- unsaturated bonds
- mixture
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000002546 isoxazolidines Chemical class 0.000 title description 5
- 150000002547 isoxazolines Chemical class 0.000 title description 3
- -1 2-propylpentyl Chemical group 0.000 claims abstract description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
- 150000001875 compounds Chemical class 0.000 claims description 27
- 238000002360 preparation method Methods 0.000 claims description 18
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 16
- QSFOWAYMMZCQNF-UHFFFAOYSA-N delmopinol Chemical compound CCCC(CCC)CCCC1COCCN1CCO QSFOWAYMMZCQNF-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 229960003854 delmopinol Drugs 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 6
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 claims description 6
- 230000002829 reductive effect Effects 0.000 claims description 5
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 238000007142 ring opening reaction Methods 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 230000002152 alkylating effect Effects 0.000 claims description 2
- 239000012320 chlorinating reagent Substances 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- 230000001131 transforming effect Effects 0.000 claims 2
- 239000003960 organic solvent Substances 0.000 claims 1
- 239000002798 polar solvent Substances 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 47
- 239000000203 mixture Substances 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 238000001704 evaporation Methods 0.000 description 10
- 230000008020 evaporation Effects 0.000 description 10
- 238000001035 drying Methods 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000007832 Na2SO4 Substances 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- RLUDGGHEFUDPLJ-UHFFFAOYSA-N 4-propylhept-1-en-4-ol Chemical compound CCCC(O)(CCC)CC=C RLUDGGHEFUDPLJ-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- SNVLJLYUUXKWOJ-UHFFFAOYSA-N methylidenecarbene Chemical compound C=[C] SNVLJLYUUXKWOJ-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- MCFJLLFFCSTWHV-UHFFFAOYSA-N 2-propylpentyl 4-methylbenzenesulfonate Chemical compound CCCC(CCC)COS(=O)(=O)C1=CC=C(C)C=C1 MCFJLLFFCSTWHV-UHFFFAOYSA-N 0.000 description 3
- RQHUZVCOAYODHV-UHFFFAOYSA-N 4-propylhepta-1,3-diene Chemical compound CCCC(CCC)=CC=C RQHUZVCOAYODHV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 0 *C(C1)ON2C1COCC2 Chemical compound *C(C1)ON2C1COCC2 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 2
- PHUWAKFNUBADFE-UHFFFAOYSA-N 3-(4-propylheptyl)morpholine Chemical compound CCCC(CCC)CCCC1COCCN1 PHUWAKFNUBADFE-UHFFFAOYSA-N 0.000 description 2
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 description 2
- HCFAJYNVAYBARA-UHFFFAOYSA-N 4-heptanone Chemical compound CCCC(=O)CCC HCFAJYNVAYBARA-UHFFFAOYSA-N 0.000 description 2
- WVLCITYWJRJQJX-UHFFFAOYSA-N 4-propylhept-1-ene Chemical compound CCCC(CCC)CC=C WVLCITYWJRJQJX-UHFFFAOYSA-N 0.000 description 2
- XZAXWRHYIPMZHS-UHFFFAOYSA-N 4-propylhept-1-yne Chemical compound CCCC(CCC)CC#C XZAXWRHYIPMZHS-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 150000001336 alkenes Chemical group 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JYZUFTSYNSOVNI-UHFFFAOYSA-N 1-bromo-4-propylheptane Chemical compound CCCC(CCC)CCCBr JYZUFTSYNSOVNI-UHFFFAOYSA-N 0.000 description 1
- MKHGVMIXRPGHOO-UHFFFAOYSA-N 2-(benzenesulfonyl)-3-phenyloxaziridine Chemical compound C=1C=CC=CC=1S(=O)(=O)N1OC1C1=CC=CC=C1 MKHGVMIXRPGHOO-UHFFFAOYSA-N 0.000 description 1
- LASHFHLFDRTERB-UHFFFAOYSA-N 2-propylpentan-1-ol Chemical compound CCCC(CO)CCC LASHFHLFDRTERB-UHFFFAOYSA-N 0.000 description 1
- OURXRFYZEOUCRM-UHFFFAOYSA-N 4-hydroxymorpholine Chemical compound ON1CCOCC1 OURXRFYZEOUCRM-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 229910020667 PBr3 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000006298 dechlorination reaction Methods 0.000 description 1
- 238000006056 electrooxidation reaction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000001030 gas--liquid chromatography Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- WMWSRIHFAVOHSW-UHFFFAOYSA-N lithium;ethane-1,2-diamine;ethyne Chemical compound [Li+].[C-]#C.NCCN WMWSRIHFAVOHSW-UHFFFAOYSA-N 0.000 description 1
- DQEUYIQDSMINEY-UHFFFAOYSA-M magnesium;prop-1-ene;bromide Chemical compound [Mg+2].[Br-].[CH2-]C=C DQEUYIQDSMINEY-UHFFFAOYSA-M 0.000 description 1
- 229940101209 mercuric oxide Drugs 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000606 toothpaste Substances 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Definitions
- the present invention concerns a new process for the preparation of delmopinol (recINN) as well as new intermediates used in the process.
- Delmopinol is a compound which has shown promising results as a plaque inhibitor. It is therefore intended to be used as an ingredient in e.g. mouthrinses and toothpastes.
- Delmopinol is a morpholino compound which is described in US patent 4,636,382. This patent also describes several manufacturing methods that can be used for the preparation of this type of morpholino compounds.
- delmopinol has been prepared in large scale and in acceptable yields according to a process comprising 16 steps. It is obvious that this manufacturing process is both time and labour consuming. It is therefore an urgent need to provide a manufacturing process that is less time and labour consuming but still gives acceptable yields also in a large scale.
- the present invention provides a solution to this problem.
- the intermediate isoxazolidines (IV) and isoxazolines (V) and delmopinol, 3-(4-propylheptyl)-4-morpholine-ethanol is prepared by a process comprising the following steps:
- the mono- and polyunsaturated 4-propylheptyl compounds I and II are prepared according to examples 1-5.
- the leaving group in step a) can be any of usual leaving groups and is suitably selected from hydroxy, alkoxy, acetoxy or tetrahydropyranyloxy.
- the morpholine nitrone III, used in step b) can be prepared from N-hydroxylmorpholine by oxidation with e.g. yellow mercuric oxide, palladium and other oxidants, or from the same precursor by photochemical or electrochemical oxidation. It may also be prepared directly from morpholine by oxidation with 2-(phenylsulfonyl)-3-phenyloxaziridine or by catalytic oxidation using hydrogen peroxide and a catalyst, e.g. selenium dioxide or sodium tungstate.
- a catalyst e.g. selenium dioxide or sodium tungstate.
- the morpholine nitrone is too unstable to be isolated and is thus used directly for reaction with the unsaturated compounds I and II.
- the compounds IV-anti and IV-syn are produced according to examples 6-12 in acceptable yields, and the unreacted starting material is easy to recover and recycle in the process.
- the compounds formed are diastereomers where IV-anti accounts for 90-98% and IV-syn for 2-10%.
- the stereochemistry of the adducts is based on analogy. See e.g. C. Hootelé et al., Bull.Soc.Chim.Belg., 1987, 96, 57 and references cited therein.
- the stereochemistry of compounds IV, as well as the degree of unsaturation, is not of importance in view of the total synthesis. All compounds IV converge to the same final product through the following steps.
- Step c) can be carried out by treatment of compound IV and V, preferably with an acid e.g. p-toluenesulfonic acid, in a lower alkohol, preferably isopropanol, in a reductive milieu.
- an acid e.g. p-toluenesulfonic acid
- a lower alkohol preferably isopropanol
- This consists of a catalyst, preferably Pd-C, under H2-pressure, preferably 3-7 atm.
- Step d) is performed by reacting the reaction mixture from step c) with a chlorinating agent, preferably by boiling with thionyl chloride.
- step e) the compounds from step d) are dechlorinated by hydrogenation, preferably with Raney-Ni as catalyst.
- step f) the compound VIa is alkylated, preferably by treatment with chloroethanol and potassium iodide and, at intervals, potassium hydroxide to give the desired 3-(4-propylheptyl)-4-morpholine-ethanol.
- 1-5 concerns the preparation of the terminal alkenes/alkynes.
- Examples 6-12 concerns the preparation of isoxazolidines (IV) and isoxazolines (V), and examples 13-15 the final preparation of delmopinol.
- GC showed that it was composed of 47% of cis/trans-4-propyl-1,4-heptadiene (not separated) and 46% of 4-propyl-1,3-heptadiene.
- the 1,4- and 1,3-isomers were separated by preparative gas-liquid chromatography (Perkin Elmer F21) on a 12 m X 8 mm column with 20% Carbowax 20M, 180°C and 1.9 atm nitrogen pressure.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Photoreceptors In Electrophotography (AREA)
- Luminescent Compositions (AREA)
- Treatments For Attaching Organic Compounds To Fibrous Goods (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Peptides Or Proteins (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Description
- The present invention concerns a new process for the preparation of delmopinol (recINN) as well as new intermediates used in the process.
Delmopinol is a compound which has shown promising results as a plaque inhibitor. It is therefore intended to be used as an ingredient in e.g. mouthrinses and toothpastes. Delmopinol is a morpholino compound which is described in US patent 4,636,382. This patent also describes several manufacturing methods that can be used for the preparation of this type of morpholino compounds. Up to now delmopinol has been prepared in large scale and in acceptable yields according to a process comprising 16 steps. It is obvious that this manufacturing process is both time and labour consuming. It is therefore an urgent need to provide a manufacturing process that is less time and labour consuming but still gives acceptable yields also in a large scale. - The present invention provides a solution to this problem.
- According to the invention the intermediate isoxazolidines (IV) and isoxazolines (V) and delmopinol, 3-(4-propylheptyl)-4-morpholine-ethanol is prepared by a process comprising the following steps:
- a) Preparation of mono- and polyunsaturated 4-propylheptyl compounds I and II, with a terminal olefinic or acetylenic bond.
I: CH₂=CH-R II: CH≡C-R
wherein R is 2-propylpentyl optionally having one, two or three internal unsaturated bonds, or
2-substituted-2-propylpentyl optionally having one or two internal unsaturated bonds, wherein the 2-substituent is a leaving group. - b) Reacting mono- and polyunsaturated 4-propylheptyl compounds (I and II) with morpholine nitrone (III)
- c) Reductive ringopening of the compounds IV and V to the compounds VIa, VIb and VIc having the formulas:
- d) Tranferring VIb and VIc to the corresponding chloroanalogs.
- e) Transferring the compounds of step d) to the compound VIa and
- f) Alkylating the compound VIa to 3-(4-propylheptyl)-4-morpholine-ethanol (delmopinol).
- The mono- and polyunsaturated 4-propylheptyl compounds I and II are prepared according to examples 1-5.
- The leaving group in step a) can be any of usual leaving groups and is suitably selected from hydroxy, alkoxy, acetoxy or tetrahydropyranyloxy.
- The morpholine nitrone III, used in step b) can be prepared from N-hydroxylmorpholine by oxidation with e.g. yellow mercuric oxide, palladium and other oxidants, or from the same precursor by photochemical or electrochemical oxidation. It may also be prepared directly from morpholine by oxidation with 2-(phenylsulfonyl)-3-phenyloxaziridine or by catalytic oxidation using hydrogen peroxide and a catalyst, e.g. selenium dioxide or sodium tungstate.
- The morpholine nitrone is too unstable to be isolated and is thus used directly for reaction with the unsaturated compounds I and II.
- The compounds IV-anti and IV-syn (as racemates) are produced according to examples 6-12 in acceptable yields, and the unreacted starting material is easy to recover and recycle in the process. The compounds formed are diastereomers where IV-anti accounts for 90-98% and IV-syn for 2-10%. The stereochemistry of the adducts is based on analogy. See e.g. C. Hootelé et al., Bull.Soc.Chim.Belg., 1987, 96, 57 and references cited therein. The stereochemistry of compounds IV, as well as the degree of unsaturation, is not of importance in view of the total synthesis. All compounds IV converge to the same final product through the following steps.
- Step c) can be carried out by treatment of compound IV and V, preferably with an acid e.g. p-toluenesulfonic acid, in a lower alkohol, preferably isopropanol, in a reductive milieu. This consists of a catalyst, preferably Pd-C, under H₂-pressure, preferably 3-7 atm.
- Step d) is performed by reacting the reaction mixture from step c) with a chlorinating agent, preferably by boiling with thionyl chloride.
- In step e) the compounds from step d) are dechlorinated by hydrogenation, preferably with Raney-Ni as catalyst.
- In step f) finally, the compound VIa is alkylated, preferably by treatment with chloroethanol and potassium iodide and, at intervals, potassium hydroxide to give the desired 3-(4-propylheptyl)-4-morpholine-ethanol.
- The most important aspect of this invention concerns the intermediates IV and V, as defined in the claims, and the preparation thereof, as these are key intermediates in the process for producing delmopinol.
- The invention is further illustrated by the following examples, of which 1-5 concerns the preparation of the terminal alkenes/alkynes. Examples 6-12 concerns the preparation of isoxazolidines (IV) and isoxazolines (V), and examples 13-15 the final preparation of delmopinol.
- To 100 g of 4-propylheptyl bromide in 400 ml of benzene was added 90 g of t-BuOK in 300 ml of DMSO. The temperature was kept below 50°C during the addition. The mixture was stirred for 2 hrs and 600 ml of water was added. The organic phase was separated and the aqueous phase extracted with petroleumether (b.p. 40-60°). The combined organic phases were washed with water and brine. After drying with Na₂SO₄ and evaporation the residue was distilled. Yield: 23.2 g (b.p. 56-59°C/75 Torr). ¹H-NMR(CDCl₃): δ 0.9(6H,CH₃), 1.2(9H,CH₂,CH), 2.0(2H,CH₂C=C), 4.8-5.1(2H,CH₂=C), 5.5-6.0(1H,CH=C)
- To 80 g of PBr₃ in 250 ml of dry diethyl ether was slowly added 46 g of 4-hydroxy-4-propyl-1-heptene at -30°C to -20°C. After the addition the temperature was kept at -25°C to -10°C another 2 hrs and then at +5°C for 15 hrs. The reaction mixture was poured on ice (500 g) and diethyl ether (500 ml) was added. The ether phase was separated and washed with NaHCO₃-solution (2X250 ml), dried with MgSO₄ and evaporated. The residue (60.0 g) was taken up in 250 ml of benzene and 94 g of 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5) and refluxed for 2 hrs. After cooling 1000 ml of diethyl ether was added and the ether solution washed with 5M HCl (2X300 ml) and water (3X250 ml), dried with MgSO₄ and evaporated. The residue (38.2 g) was distilled and the fraction 48-56°C/8 Torr was 30.6 g. GC showed that it was composed of 47% of cis/trans-4-propyl-1,4-heptadiene (not separated) and 46% of 4-propyl-1,3-heptadiene. The 1,4- and 1,3-isomers were separated by preparative gas-liquid chromatography (Perkin Elmer F21) on a 12 m X 8 mm column with 20% Carbowax 20M, 180°C and 1.9 atm nitrogen pressure.
¹H-NMR(CDCl₃): - Ib:
- δ 0.9(6H,CH₃), 1.3-1.5(4H,CH₂CC=C), 1.9-2.2(4H,CH₂C=C), 4.9-5.1(2H,CH₂=C), 5.8-5.9(1H,C=CHC=6), 6.5-6.7(1H,C=CCH=C)
- Ic:
- δ 0.8-0.9(6H,CH₃), 1.3-1.5(2H,CH₂CC=C), 1.9-2.1(4H,CH₂C=C), 2.6-2.8(2H,C=CCH₂C=C), 4.9-5.1(2H,CH₂=C), 5.1-5.3(1H,CH=C), 5.6-5.9(1H,CH=C)
- 113 g of 4-heptanone in 1000 ml of dry diethyl ether was slowly added to a solution of allylmagnesium bromide, prepared from 36.5 g of Mg and 178 g of allyl bromide in 500 ml dry diethyl ether. After the addition the mixture was refluxed for 10 hrs. The reaction mixture was poured on a mixture of 150 g ice, 450 ml of 20% NH₄Cl and 350 ml of 5M HCl. The ether phase was separated and the water phase extracted with diethyl ether (3x100 ml). The combined organic phases were then washed with a Na₂CO₃-solution and water, dried with Na₂SO₄ and evaporated. The residue was distilled. Yield: 142 g (b.p. 38-40°C/0.1 torr) ¹H-NMR(CDCl₃): δ 0.9(6H,CH₃), 1.3-1.6(9H,CH₂,OH), 2.1-2.3 (CH₂C=C), 5.0-5.2(CH₂=C), 5.6-6.1(CH=C)
- To a mixture of 52 g 2-propylpentanol and 86 g of p-toluenesulfonic acid in 175 ml of chloroform was added at 0-3°C and under N₂-atmosphere 48 g of pyridine. The mixture was kept at 0°C for 30 minutes and at room temperature for 19 hrs. After cooling the reaction mixture, 3M HCl (300 ml) was added. The organic phase was separated and washed with water and brine. Drying with Na₂SO₄ and evaporation gives 110 g of 2-propylpentyl tosylate.
¹H-NMR(CDCl₃): δ 0.8(6H,CH₃), 1.1-1.8(9H,CH₂,CH), 2.4(3H,ArCH₃), 3.9(2H,OCH₂), 7.2-7.9(4H,ArH) - 18.4 g of lithium acetylide ethylenediamine complex was charged in an argon-flushed flask. DMSO was then added (100 ml) and the mixture cooled to 15°C. 50 g of 2-propylpentyl p-toluenesulfonate was slowly added. After the addition the mixture was stirred at room temperature for 1 hr and then 50 ml of water was added carefully with vigorous stirring (the temperature was kept below 35°C). The mixture was poured into 600 ml of water and extracted with hexane (3X100 ml). The combined hexane phases were washed with brine and dried with Na₂SO₄. The hexane was distilled off and the residue distilled at reduced pressure. Yield 13.1 g (b.p 75-80°C/85 Torr).
¹H-NMR(CDCl₃): δ 0.9(6H,CH₃), 1.3(9H,CH₂,CH), 1.9(1H,CH≡C), 2.2(2H,CH₂C≡C) - To a mixture of the terminal alkene/alkyne (10 g), morpholine (19 g) and Na₂WO₄,2H₂0 (2.7 g) in methanol (50 g) and ethanol (50 g) was added 35% H₂O₂ (43 g) at a rate to keep the temperature at 50-60°C. Additional ethanol (100 ml) was added and the mixture kept at 50-60°C for 18 hrs. Most of the methanol/ethanol was evaporated in vacuo whereupon water (300 ml) was added and the mixture extracted with diethyl ether (4X50 ml). The organic phase was washed with water and brine. Drying with Na₂SO₄ and evaporation gives the isoxazolidines(IV)/isoxazoline(V).
(Other combinations of solvents are possible e.g with CHCl₃, toluene and CH₃CCl₃.) - 70 g of 35% H₂O₂ was added to a mixture of 31 g of morpholine, 125 ml of methanol, 125 ml of ethanol, 19 g of 4-hydroxy-4-propyl-1-heptene and 4.8 g of Na₂WO₄,2H₂O at a rate to keep the temperature at 50-80°C. An additional amount of 200 ml of ethanol was added and the mixture was kept at 50-60°C for 18 hrs. Most of the methanol/ethanol was evaporated in good vacuum, whereupon 600 ml of water was added and the mixture was extracted with ether (4x200 ml). The ether phase was treated with 5M HCl (4x100 ml) and 13.5 g of the starting material was recovered. The acidic aqueous phase was alkalized and extracted with ether. Drying with Na₂SO₄ and evaporation gave 5.9 g of IVd (90% anti + 10% syn).
- 735 g of 30% H₂O₂ was added to 330 g of morpholine and 52 g of Na₂WO₄,2H₂O in 400 ml of water, slowly under cooling. The temperature of the reaction mixture was kept below 20°C. One half of this nitrone mixture was then added to a refluxing mixture of 100 g of 4-hydroxy-4-propyl-1-heptene and 900 ml of methanol. After the addition refluxing was continued for 2.5 hrs whereupon the second half of the nitrone mixture was added and refluxing continued for another 2.5 hrs. After cooling the mixture was extracted with toluene (750 ml). The toluene mixture was extracted with 5M HCl (650 ml). From the organic phase 57 g of starting material, 4-hydroxy-4-propyl-1-heptene, was recovered. The aqueous phase was adjusted to pH 8.8 with 5M NaOH and extracted with toluene (500 ml). After drying with Na₂SO₄ and evaporation 37 g of IVd was recovered as syn-anti mixture.
- Further examples 9-12 were prepared persuant to the process described in Example 6. These are presented in table I.
-
- A mixture of 10 g of isoxazolidine IVd, 27 g of p-toluenesulfonic acid and 1.5 g of 10% Pd-C in 100 ml of isopropanol was shaken in a Parr bottle at 70-80°C and 3-7 atm of H₂ for 15 hrs. After cooling, the reaction mixture was filtered and the isopropanol was evaporated in a good vacuum. An excess of 5M NaOH was added and the mixture was extracted with diethyl ether. After drying and evaporation 8.8 g of a mixture of VIa, VIb and VIc (R= 2-propylpentyl) was recovered.
- 15 ml of thionyl chloride was added to 5.0 g of a mixture of compounds VIa, VIb and VIc (R= 2-propylpentyl) in 7 ml of chloroform and the mixture was stirred at 20°C for 3 hrs and refluxed for 1 hr. After evaporation 5M NaOH (25 ml) was added and the mixture was extracted with diethyl ether (3x15 ml). The combined ether phases were washed with water and brine. Drying and evaporation gave 4.8 g of the chloro-analogs and VIa.
- This mixture, together with 5 g of Raney-Ni catalyst, 5 g of triethylamine and 250 ml of dioxane, was hydrogenated at 100°C and 120 atm of H₂ for 24 hrs. The reaction mixture was filtered through Celite and evaporated. 30 ml of 5M NaOH was added and the mixture extracted with diethyl ether (3x15 ml). After drying and evaporation 4.3 g of pure 3-(4-propylheptyl)-morpholine was recovered.
- A mixture of 2.5 g of 3-(4-propylheptyl)morpholine, 3.5 g of chloroethanol, 1.1 g of potassium iodide and 7 ml of ethanol was refluxed for 5 hrs. Then 0.3 g of KOH in 1.5 ml of ethanol was added and refluxing continued for 2 hrs when another 0.2 g of KOH in 1.0 ml of ethanol was added. Refluxing for 7 hrs was followed by a third addition of 0.1 g of KOH in 0.5 ml of ethanol. After another 2 hrs of refluxing the solvent was evaporated and 10 ml of water was added. The mixture was extracted with diethyl ether (3x10 ml) and the combined organic phases were washed with brine. After drying and evaporation 2.5 g of 3-(4-propylheptyl)-4-morpholine-ethanol was recovered.
Claims (9)
- Compounds according to claim 1 characterized in that the leaving group is selected from hydroxy, alkoxy, acetoxy or tetrahydropyranyloxy.
- Compounds according to claim 1 characterized in that it has formula IV, wherein R is selected from the group consisting of 2-propylpentyl, 2-propyl-1-pentenyl, 2-propyl-2-pentenyl or 2-hydroxy-2-propylpentyl.
- Compounds according to claim 1 characterized in that it has formula V, wherein R is 2-propylpentyl.
- A method for preparing compounds having the general formulas IV and V,
2-substituted-2-propylpentyl, optionally with one or two internal unsaturated bonds, wherein the 2-substituent is a leaving group, with a morpholine nitrone, III: - A method for the preparation of delmopinol using compounds IV and V,
2-subsituted-2-propylpentyl, optionally with one or two internal unsaturated bonds, wherein the 2-substituent is a leaving group, bya) reductive ringopening of compounds IV and V, by treatment with hydrogen in the presence of a catalyst and acid in a lower alkohol, to produce compounds VIa, VIb and VIc having the formulas:b) transforming VIb and VIc, as defined in step a) to the corresponding chloroanalogs by treatment with a chlorinating agent in an organic solvent;c) transforming the compounds of step b) by reduction with hydrogen and a catalyst to the compound VIa, as defined in step a) and - Process according to claim 6 characterized in that the leaving group is selected from hydroxy, alkoxy, acetoxy or tetrahydropyranyloxy.
- Process according to claim 6 characterized in that the intermediate has formula IV and that R is selected from the group consisting of 2-propylpentyl, 2-propyl-1-pentenyl, 2-propyl-2-pentenyl or 2-hydroxy-2-propylpentyl.
- Process according to claim 6 characterized in that the intermediate has formula V and that R is 2-propylpentyl.
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SE8901837 | 1989-05-24 | ||
SE8901837A SE8901837D0 (en) | 1989-05-24 | 1989-05-24 | SUBSTITUTED ISOXAZOLIDINES AND ISOXAZOLINES |
SE8901838A SE8901838D0 (en) | 1989-05-24 | 1989-05-24 | NEW PROCESS AND INTERMEDIATES |
SE8901838 | 1989-05-24 | ||
PCT/SE1990/000323 WO1990014342A1 (en) | 1989-05-24 | 1990-05-14 | Substituted isoxazolidines and isoxazolines |
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US5147632A (en) * | 1990-10-31 | 1992-09-15 | Warner-Lambert Company | Anti-plaque compositions comprising a combination of morpholinoamino alcohol and chelating agent |
GB9226857D0 (en) * | 1992-12-23 | 1993-02-17 | Boyd Edward A | Pharmaceutical compositions |
US5552757A (en) * | 1994-05-27 | 1996-09-03 | Littelfuse, Inc. | Surface-mounted fuse device |
US6878004B2 (en) * | 2002-03-04 | 2005-04-12 | Littelfuse, Inc. | Multi-element fuse array |
ATE348818T1 (en) | 2003-06-12 | 2007-01-15 | Btg Int Ltd | CYCLIC HYDROXYLAMINES AS PSYCHOACTIVE COMPOUNDS |
JP2007512185A (en) * | 2003-11-26 | 2007-05-17 | リッテルフューズ,インコーポレイティド | Electrical protection device for vehicle and system using electrical protection device for vehicle |
GB0523435D0 (en) | 2005-11-17 | 2005-12-28 | Sinclair Pharmaceuticals Ltd | Process |
PT1951374T (en) | 2005-11-22 | 2017-06-08 | Merial Inc | Treatment of sub-gingival pocket infections |
GB0602424D0 (en) | 2006-02-07 | 2006-03-22 | Sinclair Pharmaceuticals Ltd | Compounds |
GB0604018D0 (en) | 2006-02-28 | 2006-04-05 | Sinclair Pharmaceuticals Ltd | Method |
GB0615814D0 (en) | 2006-08-09 | 2006-09-20 | Sinclair Pharmaceuticals Ltd | Medicament |
GB201105162D0 (en) | 2011-03-28 | 2011-05-11 | Lane Jonathan | Improved deodorant formulations |
IT201600130729A1 (en) | 2016-12-23 | 2018-06-23 | Lundbeck Pharmaceuticals Italy S P A | PROCESS FOR THE PRODUCTION OF DELMOPINOL INTERMEDIATES |
IT201600130642A1 (en) | 2016-12-23 | 2018-06-23 | Lundbeck Pharmaceuticals Italy S P A | PROCESS FOR THE PRODUCTION OF 2 (3 ALCHILMORPHOLIN) -ETAN-1-OLO |
IT201600130538A1 (en) * | 2016-12-23 | 2018-06-23 | Lundbeck Pharmaceuticals Italy S P A | PROCESS FOR DELMOPINOL PRODUCTION |
IT201700076821A1 (en) | 2017-08-24 | 2019-02-24 | Lundbeck Pharmaceuticals Italy S P A | NEW SALT OF DELMOPINOL |
CA3169675C (en) * | 2020-01-31 | 2024-05-28 | You First Services, Inc. | Methods of making delmopinol and salts thereof |
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JPS59164762A (en) * | 1983-03-09 | 1984-09-17 | Univ Osaka | Synthesis of nitron form secondary amine |
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BULLETIN DES SOCIETES CHIMIQUES BELGES, vol. 96, 1987, page 57; C. HOOTELE et al.: "The cycloaddition reaction between styrene and 2,3,4,5-tetrahydropyridine 1-oxide" * |
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